Emtricitabine And Tenofovir Disoproxil Fumarate

1 )] . 3 )] . 4 )] . 5 )]. 6 )] . • In HIV-1 infected patients, the most common adverse reactions (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.

1 ) • In HIV-1 uninfected adults in PrEP trials, adverse reactions that were reported by more than 2% of emtricitabine and tenofovir disoproxil fumarate participants and more frequently than by placebo participants were headache, abdominal pain, and weight decreased.

1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Subjects Clinical Trials in Adult Subjects In Study 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either FTC+TDF (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks.

The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Table 3 provides the treatment-emergent adverse reactions (Grades 2 to 4) occurring in greater than or equal to 5% of subjects treated in any treatment group.

Skin discoloration, manifested by hyperpigmentation, occurred in 3% of subjects taking FTC+TDF, and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Table 3 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥5% in Any Treatment Group in Study 934 (0 to 144 Weeks) FTC+TDF+EFV b AZT/3TC+EFV N=257 N=254 Fatigue Depression Nausea Diarrhea Dizziness Upper respiratory tract infections Sinusitis Rash event c Headache Insomnia Nasopharyngitis Vomiting 9% 9% 9% 9% 8% 8% 8% 7% 6% 5% 5% 2% 8% 7% 7% 5% 7% 5% 4% 9% 5% 7% 3% 5% a.

Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. From Weeks 96 to 144 of the trial, subjects received emtricitabine and tenofovir disoproxil fumarate with efavirenz in place of FTC+TDF with efavirenz.

c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular.

Laboratory Abnormalities:

Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of TDF and/or FTC (Table 4). 0 mg/dL) 0% 4% Hyperglycemia (>250 mg/dL) 2% 1% Hematuria (>75 RBC/HPF) 3% 2% Glycosuria (≥3+) <1% 1% Neutrophils (<750/mm 3 ) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% a.

From Weeks 96 to 144 of the trial, subjects received emtricitabine and tenofovir disoproxil fumarate with efavirenz in place of FTC+TDF with efavirenz.

Clinical Trials in Pediatric Subjects Emtricitabine:

In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with FTC in the larger of two open-label, uncontrolled pediatric trials (N=116).

Tenofovir Disoproxil Fumarate:

In pediatric clinical trials (Studies 352 and 321) conducted in 184 HIV-1 infected subjects 2 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with TDF were consistent with those observed in clinical trials of TDF in adults.

In Study 352 (2 to less than 12 years of age), 89 pediatric subjects received TDF for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy.

5 )] . Total body BMD gain at Week 48 was less in the TDF group compared to the stavudine (d4T) or zidovudine (AZT) treatment groups. The mean rate of BMD gain in lumbar spine was similar between treatment groups. One TDF-treated subject and none of the d4T- or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48.

338 for total body in the 64 subjects who were treated with TDF for 96 weeks. In Study 321 (12 to less than 18 years of age), the mean rate of BMD gain at Week 48 was less in the TDF compared to the placebo treatment group. Six TDF-treated subjects and one placebo-treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48.

458 for total body in the 28 subjects who were treated with TDF for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected. Adverse Reactions from Clinical Trial Experience in Uninfected Subjects Taking Emtricitabine and Tenofovir Disoproxil Fumarate for HIV-1 PrEP Clinical Trials in Adult Subjects The safety profile of emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP was comparable to that observed in clinical trials of HIV-infected subjects based on two randomized placebo-controlled clinical trials (iPrEx, Partners PrEP) in which 2,830 HIV-1 uninfected adults received emtricitabine and tenofovir disoproxil fumarate once daily for HIV-1 PrEP.

Subjects were followed for a median of 71 weeks and 87 weeks, respectively. Table 5 provides a list of selected adverse events that occurred in 2% or more of subjects in any treatment group in the iPrEx trial, with an incidence greater than placebo.

Table 5 Selected Adverse Events (All Grades) Reported in ≥2% in Any Treatment Group in the iPrEx Trial and Greater than Placebo FTC/TDF Placebo (N=1251) (N=1248) Headache 7% 6% Abdominal pain 4% 2% Weight decreased 3% 2% In the Partners PrEP trial, the frequency of adverse events in the emtricitabine and tenofovir disoproxil fumarate treatment group was generally either less than or the same as in the placebo group.

Laboratory Abnormalities:

Table 6 provides a list of Grade 2 to 4 laboratory abnormalities observed in the iPrEx and Partners PrEP trials. Six subjects in the TDF-containing arms of the Partners PrEP trial discontinued from the trial due to an increase in serum creatinine compared with no discontinuations in the placebo group.

One subject in the emtricitabine and tenofovir disoproxil fumarate arm of the iPrEx trial discontinued from the trial due to an increase in serum creatinine and another subject discontinued due to low serum phosphorus. Grades 2 to 3 proteinuria (2 to 4+) and/or glycosuria (3+) occurred in less than 1% of subjects treated with emtricitabine and tenofovir disoproxil fumarate in the iPrEx trial and Partners PrEP trial.

4 mg/dL) 1% 2% 2% 2% Neutrophils (<750/mm 3 ) <1% <1% 5% 3% a. Grading is per DAIDS criteria.

Changes in Bone Mineral Density:

In clinical trials of HIV-1 uninfected individuals, decreases in BMD were observed. 0% across total hip, spine, femoral neck, and trochanter in the emtricitabine and tenofovir disoproxil fumarate group compared with the placebo group, which returned toward baseline after discontinuation of treatment.

Thirteen percent of emtricitabine and tenofovir disoproxil fumarate-treated subjects versus 6% of placebo-treated subjects lost at least 5% of BMD at the spine during treatment. 4% in the placebo group. 3 )]. 4 )] . Clinical Trials in Adolescent Subjects In a single-arm, open-label clinical trial (ATN113), in which 67 HIV-1 uninfected adolescent (15 to 18 years of age) men who have sex with men received emtricitabine and tenofovir disoproxil fumarate once daily for HIV-1 PrEP, the safety profile of emtricitabine and tenofovir disoproxil fumarate was similar to that observed in adults.

4 )] . 72% for total body. One subject had significant (greater than or equal to 4%) total body BMD loss at Week 24. 2 for total body at Week 48. Three subjects showed a worsening (change from > −2 to ≤ −2) from baseline in their lumbar spine or total body BMD Z-scores at Week 24 or 48.

Interpretation of these data, however, may be limited by the low rate of adherence to emtricitabine and tenofovir disoproxil fumarate by Week 48. 2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TDF.

No additional adverse reactions have been identified during postapproval use of FTC. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders allergic reaction, including angioedema Metabolism and Nutrition Disorders lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders dyspnea Gastrointestinal Disorders pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT) Skin and Subcutaneous Tissue Disorders rash Musculoskeletal and Connective Tissue Disorders rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

5 WARNINGS AND PRECAUTIONS • Comprehensive management to reduce the risk of acquiring HIV-1 when emtricitabine and tenofovir disoproxil fumarate tablet is used for HIV-1 PrEP: Use as part of a comprehensive prevention strategy including other prevention measures; strictly adhere to dosing schedule.

2 ) • Management to reduce the risk of acquiring HIV-1 drug resistance when emtricitabine and tenofovir disoproxil fumarate tablet is used for HIV-1 PrEP: refer to full prescribing information for additional detail. 2 ) • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome.

Avoid administering emtricitabine and tenofovir disoproxil fumarate with concurrent or recent use of nephrotoxic drugs. 3 ) • Immune reconstitution syndrome during treatment of HIV-1 infection: May necessitate further evaluation and treatment.

4 ) • Decreases in bone mineral density (BMD): Consider assessment of BMD in individuals with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. 5 ) • Lactic acidosis/severe hepatomegaly with steatosis: Discontinue emtricitabine and tenofovir disoproxil fumarate tablets in individuals who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

1 )] . , liver decompensation and liver failure) have been reported in HBV-infected individuals who have discontinued emtricitabine and tenofovir disoproxil fumarate. Individuals infected with HBV who discontinue emtricitabine and tenofovir disoproxil fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

If appropriate, anti-hepatitis B therapy may be warranted, especially in individuals with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. HBV-uninfected individuals should be offered vaccination.

2 Comprehensive Management to Reduce the Risk of Sexually Transmitted Infections, Including HIV-1, and Development of HIV-1 Resistance When Emtricitabine and Tenofovir Disoproxil Fumarate Is Used for HIV-1 PrEP Use emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP to reduce the risk of HIV-1 infection as part of a comprehensive prevention strategy that includes other prevention measures, including adherence to daily administration and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs).

The time from initiation of emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown. Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including but not limited to condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network.

, consistent and correct condom use, knowledge of partner(s)’ HIV-1 status, including viral suppression status, regular testing for STIs that can facilitate HIV-1 transmission). Inform uninfected individuals about and support their efforts in reducing sexual risk behavior.

Use emtricitabine and tenofovir disoproxil fumarate to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-negative. 4 )] ; therefore, care should be taken to minimize the risk of initiating or continuing emtricitabine and tenofovir disoproxil fumarate before confirming the individual is HIV-1 negative.

• Some HIV-1 tests only detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. , fever, fatigue, myalgia, skin rash). • If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection.

While using emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP, HIV-1 testing should be repeated at least every 3 months, and upon diagnosis of any other STIs. • If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following a potential exposure event, convert the HIV-1 PrEP regimen to an HIV treatment regimen until negative infection status is confirmed using a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection.

Counsel HIV-1 uninfected individuals to strictly adhere to the once daily emtricitabine and tenofovir disoproxil fumarate dosing schedule. The effectiveness of emtricitabine and tenofovir disoproxil fumarate in reducing the risk of acquiring HIV-1 is strongly correlated with adherence, as demonstrated by measurable drug levels in clinical trials of emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP.

4 )]. 3 New Onset or Worsening Renal Impairment Emtricitabine and tenofovir are principally eliminated by the kidney. 2 )] . Prior to initiation and during use of emtricitabine and tenofovir disoproxil fumarate, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals.

In individuals with chronic kidney disease, also assess serum phosphorus. 1 )] . Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF.

Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in individuals at risk of renal dysfunction.

6 )] . No safety or efficacy data are available in patients with renal impairment who received emtricitabine and tenofovir disoproxil fumarate using these dosing guidelines, so the potential benefit of emtricitabine and tenofovir disoproxil fumarate therapy should be assessed against the potential risk of renal toxicity.

Emtricitabine and tenofovir disoproxil fumarate is not recommended in patients with estimated creatinine clearance below 30 mL/min or patients requiring hemodialysis. HIV-1 PrEP Emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP is not recommended in uninfected individuals with estimated creatinine clearance less than 60 mL/min.

6 )] . 4 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including emtricitabine and tenofovir disoproxil fumarate. During the initial phase of combination antiretroviral treatment, HIV-1 infected patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

1 )] . Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF. Clinical trials evaluating TDF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients.

In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1 infected pediatric subjects as compared to the control groups.

Similar trends were observed in adolescent subjects aged 12 years to less than 18 years treated for chronic hepatitis B. In all pediatric trials, skeletal growth (height) appeared to be unaffected. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.

Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial.

If bone abnormalities are suspected, appropriate consultation should be obtained. 1 )] . Arthralgia and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. 3 )] . 6 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including FTC and TDF, components of emtricitabine and tenofovir disoproxil fumarate tablets, alone or in combination with other antiretrovirals.

Treatment with emtricitabine and tenofovir disoproxil fumarate should be suspended in any individual who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

2 )] . See Table 7 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with emtricitabine and tenofovir disoproxil fumarate; review concomitant medications during therapy with emtricitabine and tenofovir disoproxil fumarate; and monitor for adverse reactions associated with the concomitant drugs.

2 )] . Emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP are contraindicated in individuals with unknown or positive HIV-1 status. ( 4 )